title: A monovalent anti-human CD28 domain antibody antagonist: preclinical efficacy and safety.
abstract: Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, we describe anti-human CD28 receptor antagonist domain Abs (dAbs) that are specific for human CD28. These dAbs are potent inhibitors of T cell activation, with an EC50 of 35 ± 14 ng/ml for inhibition of proliferation. The EC50 of 53 ± 11 ng/ml in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation. The anti-CD28 dAb is equipotent in the inhibition of CD80- and CD86-mediated T cell proliferation and does not interfere with CTLA-4-mediated downmodulation of CD86 expression on APCs. The anti-CD28 dAbs are monomeric and do not demonstrate any evidence of agonism or costimulatory activity. In cynomolgus monkeys, the anti-CD28 dAb demonstrated pharmacodynamic activity, as measured by the inhibition of a T cell-dependent Ab response, without evidence of T cell depletion or cytokine release. Furthermore, there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamic activity. Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases.
authors.affiliation: Immunology Discovery, Bristol-Myers Squibb, Princeton, NJ 08543;
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Suchard
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Davis
authors.forename: Selena
authors.initials: S
authors.lastname: Kansal
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Stetsko
authors.forename: Ruth
authors.initials: R
authors.lastname: Brosius
authors.forename: James
authors.initials: J
authors.lastname: Tamura
authors.forename: Lumelle
authors.initials: L
authors.lastname: Schneeweis
authors.forename: James
authors.initials: J
authors.lastname: Bryson
authors.forename: Theodora
authors.initials: T
authors.lastname: Salcedo
authors.forename: Haiqing
authors.initials: H
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Fleener
authors.forename: Olga
authors.initials: O
authors.lastname: Ignatovich
authors.forename: Christopher
authors.initials: C
authors.lastname: Plummer
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Steven G
authors.initials: SG
authors.lastname: Nadler
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D001327:Autoimmune Diseases / Q000628:therapy; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology; D049109:Cell Proliferation; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008252:Macaca fascicularis; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000906:Antibodies; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human